Browse by author
Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 The AuthorsA molecular hallmark in Parkinson's disease (PD) pathogenesis are α-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of α-synuclein. Here, we investigated the effects of CDNF on α-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with α-synuclein with a KD = 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils and induces the formation of insoluble phosphorylated α-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with α-synuclein fibrils, though it did not reduce the number of phosphorylated α-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with α-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.
Author(s): Albert K, Raymundo DP, Panhelainen A, Eesmaa A, Shvachiy L, Araujo GR, Chmielarz P, Yan X, Singh A, Cordeiro Y, Palhano FL, Foguel D, Luk KC, Domanskyi A, Voutilainen MH, Huttunen HJ, Outeiro TF, Saarma M, Almeida MS, Airavaara M
Publication type: Article
Publication status: Published
Journal: Molecular Therapy
Year: 2021
Volume: 29
Issue: 9
Pages: 2821-2840
Print publication date: 01/09/2021
Online publication date: 01/05/2021
Acceptance date: 27/04/2021
Date deposited: 24/08/2023
ISSN (print): 1525-0016
ISSN (electronic): 1525-0024
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ymthe.2021.04.035
DOI: 10.1016/j.ymthe.2021.04.035
PubMed id: 33940158
Altmetrics provided by Altmetric
